Vascular endothelial cell growth factor (VEGF) is a mitogen that promotes angiogenesis associated with physiological and pathological processes (cancer, rheumatoid arthritis, retinopathies). The first step in VEGF action is binding to either of two receptor tyrosine kinases, Flk-1 and Flt-1. The roles of these receptors in mediating cellular responses to VEGF have not been well defined nor have the signaling pathways that promote the activities of either receptor. Using ribozyme/antisense constructs that specifically target and degrade Flk-1 and Flt-1, they will isolate endothelial cells in which one or the other VEGF receptor has been knocked out. Such cells will be used to define the responses mediated by Flk-1 and Flt-1. From among the transduction pathways associated with VEGF action, they have found that phosphatidylinositol 3-kinase and mitogen activated protein kinases are especially important. The role of these systems in promoting diverse responses induced by VEGF will be defined. Finally, they have found that protein tyrosine phosphatases can positively and negatively regulate VEGF action. The role of such phosphatases, two in particular- SYP and LAR, in modulating VEGF signaling and cellular responses to VEGF will be defined.